bims-amsmem 2023-03-19 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2023‒03‒19
twelve papers selected by
Dipsikha Biswas, Københavns Universitet

AMPK activation by metformin protects against pulmonary hypertension in rats and relaxes isolated human pulmonary artery.
AMPK activation by AICAR reduces diet induced fatty liver in C57BL/6 mice.
High fructose-induced skeletal muscle insulin resistance could be alleviated by berberine via AMPD1 and ADSL.
SAPS3 subunit of protein phosphatase 6 is an AMPK inhibitor and controls metabolic homeostasis upon dietary challenge in male mice.
Amarogentin inhibits vascular smooth muscle cell proliferation and migration and attenuates neointimal hyperplasia via AMPK activation.
Vitamin D-VDR (vitamin D receptor) alleviates glucose metabolism reprogramming in lipopolysaccharide-induced acute kidney injury.
The Regulation of the AMPK/mTOR Axis Mitigates Tendon Stem/Progenitor Cell Senescence and Delays Tendon Aging.
Exercise-acclimated microbiota improves skeletal muscle metabolism via circulating bile acid deconjugation.
Effect of bempedoic acid on angiotensin-II induced hypertension and vascular tissue remodelling in renal hypertensive rats through AMPK multiple signalling pathways modulation.
Free fatty acids induce coronary microvascular dysfunction via inhibition of the AMPK/KLF2/eNOS signaling pathway.
FGF19 increases mitochondrial biogenesis and fusion in chondrocytes via the AMPKα-p38/MAPK pathway.
Proteomes from AMPK-inhibited peripheral blood mononuclear cells suppress the progression of breast cancer and bone metastasis.

Eur J Pharmacol. 2023 Mar 11. pii: S0014-2999(23)00090-0. [Epub ahead of print] 175579

AMPK activation by metformin protects against pulmonary hypertension in rats and relaxes isolated human pulmonary artery.

Heba Abdelazeem, Ly Tu, Raphaël Thuillet, Mina Ottaviani, Achraf Boulfrad, Thomas Beck, Amira Senbel, Salma Mani, Yves Castier, Alice Guyard, Alexy Tran-Dinh, Jamel El-Benna, Dan Longrois, Adam M Silverstein, Christophe Guignabert, Xavier Norel.

  Pulmonary hypertension (PH) is associated with pulmonary vasoconstriction and endothelial dysfunction leading to impaired nitric oxide (NO) and prostacyclin (PGI2) pathways. Metformin, the first line treatment for type 2 diabetes and AMP-activated protein kinase (AMPK) activator, has been recently highlighted as a potential PH treatment. AMPK activation has been reported to improve endothelial function by enhancing endothelial NO synthase (eNOS) activity and to have relaxant effects in blood vessels. In this study, we examined the effect of metformin treatment on PH as well as on NO and PGI2 pathways in monocrotaline (MCT)-injected rats with established PH. Moreover, we investigated the anti-contractile effects of AMPK activators on endothelium-denuded human pulmonary arteries (HPA) from Non-PH and Group 3 PH patients (due to lung diseases and/or hypoxia). Furthermore, we explored the interaction between treprostinil and the AMPK/eNOS pathway. Our results showed that metformin protected against PH progression in MCT rats where it reduced the mean pulmonary artery pressure, pulmonary vascular remodeling and right ventricular hypertrophy and fibrosis compared to vehicle-treated MCT rats. The protective effects on rat lungs were mediated in part by increasing eNOS activity and protein kinase G-1 expression but not through the PGI2 pathway. In addition, incubation with AMPK activators reduced the phenylephrine-induced contraction of endothelium-denuded HPA from Non-PH and PH patients. Finally, treprostinil also augmented eNOS activity in HPA smooth muscle cells. In conclusion, we found that AMPK activation can enhance the NO pathway, attenuate vasoconstriction by direct effects on smooth muscles, and reverse established MCT-induced PH in rats.

Keywords:  AMPK; Endothelial dysfunction; Metformin; Pulmonary hypertension; Vascular remodeling; Vasoconstriction

DOI:  https://doi.org/10.1016/j.ejphar.2023.175579
Tissue Cell. 2023 Mar 02. pii: S0040-8166(23)00042-3. [Epub ahead of print]82 102054

AMPK activation by AICAR reduces diet induced fatty liver in C57BL/6 mice.

Ajay Krishnan U, Periyasamy Viswanathan, Anuradha Carani Venkataraman.

  Dysregulation of 5'-adenosine monophosphate-activated protein kinase (AMPK) occurs in metabolic disorders including non-alcoholic fatty liver disease (NAFLD) which makes it a molecular target for treatment. An AMPK activator, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) alleviates NAFLD in experimental rats, however the specific mechanism remains to be explored. We aimed to study the effect of AICAR on lipid levels, oxidant-antioxidant balance, AMPK and mTOR activation and FOXO3 gene expression in liver of mice model. Fatty liver was induced in two groups of C57BL/6 mice (groups 2 and 3) by providing a high fat high fructose diet (HFFD) for 10 weeks while groups 1 and 4 animals were fed normal pellet. For the last two weeks, groups 3 and 4 were administered AICAR (150 mg/kg bw/day, i.p.) while groups 1 and 2 were administered saline. AICAR decreased fatty liver, decreased glucose and insulin in circulation, prevented the accumulation of triglycerides and collagen and ameliorated oxidative stress in HFFD fed mice. At the molecular level, AICAR upregulated FOXO3 and p-AMPK expression and reduced p-mTOR expression. AMPK activation may involve FOXO3 in protection against NAFLD. The role of AMPK, mTOR and FOXO3 crosstalk in NAFLD needs to be characterised in future.

Keywords:  AICAR; AMPK; FOXO3; Fatty liver; High fat high fructose diet; MTOR

DOI:  https://doi.org/10.1016/j.tice.2023.102054
Food Chem Toxicol. 2023 Mar 15. pii: S0278-6915(23)00133-3. [Epub ahead of print] 113731

High fructose-induced skeletal muscle insulin resistance could be alleviated by berberine via AMPD1 and ADSL.

Juanjuan Cheng, Xingdong Ma, Guangtao Yan, Qiuxia Yu, Zhen Huang, Guoshu Lin, Mengyao Li, Fengkun Guan, Ziren Su, Fang Yan, Yuhong Liu, Qingfeng Xie.

  AMP-activated protein kinase (AMPK) is a master regulator of energy homeostasis that is activated in response to an elevated intracellular AMP/ATP ratio. Although many studies have shown berberine is an AMPK activator widely used in metabolic syndrome, how to properly control AMPK activity remains obscure. Our present study aimed to examine the protective effect of berberine against fructose-induced insulin resistance in rats and L6 cells, as well as its potential activation mechanism on AMPK. The results showed that berberine effectively reversed body weight gain, Lee's index, dyslipidemia and insulin intolerance. Moreover, berberine alleviated inflammatory response, antioxidant capacity and promoted glucose uptake in vivo and in vitro. The beneficial effect was associated with upregulation of both Nrf2 and AKT/GLUT4 pathways, which were regulated by AMPK. Notably, berberine could increase the level of AMP and the ratio of AMP/ATP, then further activate AMPK. Mechanistic experiments revealed that berberine suppressed the expression of adenosine monophosphate deaminase 1 (AMPD1) and promoted the expression of adenylosuccinate synthetase (ADSL). Taken together, berberine exerted excellent therapeutic effect on insulin resistance. And its mode of action may be related to the AMP-AMPK pathway by regulating AMPD1 and ADSL.

Keywords:  ADSL; AMPD1; Berberine; Fructose; Insulin resistance

DOI:  https://doi.org/10.1016/j.fct.2023.113731
Nat Commun. 2023 Mar 13. 14(1): 1368

SAPS3 subunit of protein phosphatase 6 is an AMPK inhibitor and controls metabolic homeostasis upon dietary challenge in male mice.

Ying Yang, Michael A Reid, Eric A Hanse, Haiqing Li, Yuanding Li, Bryan I Ruiz, Qi Fan, Mei Kong.

Inhibition of AMPK is tightly associated with metabolic perturbations upon over nutrition, yet the molecular mechanisms underlying are not clear. Here, we demonstrate the serine/threonine-protein phosphatase 6 regulatory subunit 3, SAPS3, is a negative regulator of AMPK. SAPS3 is induced under high fat diet (HFD) and recruits the PP6 catalytic subunit to deactivate phosphorylated-AMPK, thereby inhibiting AMPK-controlled metabolic pathways. Either whole-body or liver-specific deletion of SAPS3 protects male mice against HFD-induced detrimental consequences and reverses HFD-induced metabolic and transcriptional alterations while loss of SAPS3 has no effects on mice under balanced diets. Furthermore, genetic inhibition of AMPK is sufficient to block the protective phenotype in SAPS3 knockout mice under HFD. Together, our results reveal that SAPS3 is a negative regulator of AMPK and suppression of SAPS3 functions as a guardian when metabolism is perturbed and represents a potential therapeutic strategy to treat metabolic syndromes.

DOI: https://doi.org/10.1038/s41467-023-36809-1
Biochim Biophys Acta Mol Basis Dis. 2023 Mar 09. pii: S0925-4439(23)00033-9. [Epub ahead of print] 166667

Amarogentin inhibits vascular smooth muscle cell proliferation and migration and attenuates neointimal hyperplasia via AMPK activation.

Fangyuan Jia, Rui Ji, Gang Qiao, Zhigang Sun, Xiaosan Chen, Zhidong Zhang.

  OBJECTIVES: Recent studies validated the expression of extraoral bitter taste receptors and established the importance of regulatory functions that are associated with various cellular biological processes of these receptors. However, the importance of bitter taste receptors' activity in neointimal hyperplasia has not yet been recognized. The bitter taste receptors activator amarogentin (AMA) is known to regulate a variety of cellular signals, including AMP-activated protein kinase (AMPK), STAT3, Akt, ERK, and p53, which are associated with neointimal hyperplasia.MATERIALS AND METHODS: The present study assessed the effects of AMA on neointimal hyperplasia and explored the potential underlying mechanisms.
RESULTS: No cytotoxic concentration of AMA significantly inhibited the proliferation and migration of VSMCs induced by serum (15 % FBS) and PDGF-BB. In addition, AMA significantly inhibited neointimal hyperplasia of the cultured great saphenous vein in vitro and ligated mouse left carotid arteries in vivo, while the inhibitory effect of AMA on the proliferation and migration of VSMCs was mediated via the activation of AMPK-dependent signaling, which could be blocked via AMPK inhibition.
CONCLUSION: The present study revealed that AMA inhibited the proliferation and migration of VSMCs and attenuated neointimal hyperplasia, both in ligated mice carotid artery and cultured saphenous vein, which was mediated via a mechanism that involved AMPK activation. Importantly, the study highlighted the potential of AMA to be explored as a new drug candidate for neointimal hyperplasia.

Keywords:  AMPK; Amarogentin; Neointimal hyperplasia; Vascular smooth muscle cell

DOI:  https://doi.org/10.1016/j.bbadis.2023.166667
Front Physiol. 2023 ;14 1083643

Vitamin D-VDR (vitamin D receptor) alleviates glucose metabolism reprogramming in lipopolysaccharide-induced acute kidney injury.

Qing Dai, Hao Zhang, Shiqi Tang, Xueqin Wu, Jianwen Wang, Bin Yi, Jishi Liu, Zhi Li, Qin Liao, Aimei Li, Yan Liu, Wei Zhang.

  Background: Our previous study showed that vitamin D (VD)-vitamin D receptor (VDR) plays a nephroprotective role in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). Recently, glucose metabolism reprogramming was reported to be involved in the pathogenesis of AKI. Objective: To investigate the role of VD-VDR in glucose metabolism reprogramming in LPS-induced AKI. Methods: We established a model of LPS-induced AKI in VDR knockout (VDR-KO) mice, renal proximal tubular-specific VDR-overexpressing (VDR-OE) mice and wild-type C57BL/6 mice. In vitro, human proximal tubular epithelial cells (HK-2 cells), VDR knockout and VDR overexpression HK-2 cell lines were used. Results: Paricalcitol (an active vitamin D analog) or VDR-OE reduced lactate concentration, hexokinase activity and PDHA1 phosphorylation (a key step in inhibiting aerobic oxidation) and simultaneously ameliorated renal inflammation, apoptosis and kidney injury in LPS-induced AKI mice, which were more severe in VDR-KO mice. In in vitro experiments, glucose metabolism reprogramming, inflammation and apoptosis induced by LPS were alleviated by treatment with paricalcitol or dichloroacetate (DCA, an inhibitor of p-PDHA1). Moreover, paricalcitol activated the phosphorylation of AMP-activated protein kinase (AMPK), and an AMPK inhibitor partially abolished the protective effect of paricalcitol in LPS-treated HK-2 cells. Conclusion: VD-VDR alleviated LPS-induced metabolic reprogramming in the kidneys of AKI mice, which may be attributed to the inactivation of PDHA1 phosphorylation via the AMPK pathway.

Keywords:  AMPK pathway; PDHA1 phosphorylation; acute kidney injury; glucose metabolism reprogramming; vitamin D; vitamin D receptor

DOI:  https://doi.org/10.3389/fphys.2023.1083643
Stem Cell Rev Rep. 2023 Mar 14.

The Regulation of the AMPK/mTOR Axis Mitigates Tendon Stem/Progenitor Cell Senescence and Delays Tendon Aging.

Guangchun Dai, Yingjuan Li, Ming Zhang, Panpan Lu, Yuanwei Zhang, Hao Wang, Liu Shi, Mumin Cao, Renwang Shen, Yunfeng Rui.

  Age-related tendon disorders are closely linked with tendon stem/progenitor cell (TSPC) senescence. However, the underlying mechanisms of TSPC senescence and promising therapeutic strategies for rejuvenation of TSPC senescence remain unclear. In this study, the senescent state of TSPCs increased with age. It was also verified that the AMPK inhibition/mTOR activation is correlated with the senescent state of TSPCs. Furthermore, a low dose of metformin mitigated TSPC senescence and restored senescence-related functions, including proliferation, colony-forming ability, migration ability and tenogenic differentiation ability at the early stage of aging. The protective effects of metformin on TSPCs were regulated through the AMPK/mTOR axis. An in vivo study showed that metformin treatment postpones tendon aging and enhances AMPK phosphorylation but reduces mTOR phosphorylation in a natural aging rat model. Our study revealed new insight and mechanistic exploration of TSPC senescence and proposed a novel therapeutic treatment for age-related tendon disorders by targeting the AMPK/mTOR axis at the early stage of aging.

Keywords:  AMPK/mTOR axis; Age-related tendon disorders; Delay aging; Metformin; Natural aging; Tendon stem/progenitor cells

DOI:  https://doi.org/10.1007/s12015-023-10526-0
iScience. 2023 Mar 17. 26(3): 106251

Exercise-acclimated microbiota improves skeletal muscle metabolism via circulating bile acid deconjugation.

Wataru Aoi, Ryo Inoue, Katsura Mizushima, Akira Honda, Marie Björnholm, Tomohisa Takagi, Yuji Naito.

  Habitual exercise alters the intestinal microbiota composition, which may mediate its systemic benefits. We examined whether transplanting fecal microbiota from trained mice improved skeletal muscle metabolism in high-fat diet (HFD)-fed mice. Fecal samples from sedentary and exercise-trained mice were gavage-fed to germ-free mice. After receiving fecal samples from trained donor mice for 1 week, recipient mice had elevated levels of AMP-activated protein kinase (AMPK) and insulin growth factor-1 in skeletal muscle. In plasma, bile acid (BA) deconjugation was found to be promoted in recipients transplanted with feces from trained donor mice; free-form BAs also induced more AMPK signaling and glucose uptake than tauro-conjugated BAs. The transplantation of exercise-acclimated fecal microbiota improved glucose tolerance after 8 weeks of HFD administration. Intestinal microbiota may mediate exercise-induced metabolic improvements in mice by modifying circulating BAs. Our findings provide insights into the prevention and treatment of metabolic diseases.

Keywords:  Microbial metabolism; Microbiome; Musculoskeletal medicine

DOI:  https://doi.org/10.1016/j.isci.2023.106251
Life Sci. 2023 Mar 15. pii: S0024-3205(23)00207-2. [Epub ahead of print] 121573

Effect of bempedoic acid on angiotensin-II induced hypertension and vascular tissue remodelling in renal hypertensive rats through AMPK multiple signalling pathways modulation.

Asmaa A Ahmed, Shimaa K Mohamed, Shahira Nofal, Engy M El Morsy, Amany A E Ahmed.

  Angiotensin II (Ang II), the effector of the renin-angiotensin system (RAS), is a key player in the pathogenesis of chronic hypertension, accompanied by vascular tissue resistance, remodelling, and damage. Chronic activation of Ang II receptor 1 (AT-1R) impairs multiple cellular targets implicated in cellular protection and survival, including adenosine Monophosphate-activated protein kinase (AMPK) signalling. In addition, it induces oxidative damage, endoplasmic reticulum (ER) stress, and fibrotic changes in resistance vessels. Our study investigated the antihypertensive and antifibrotic effects of bempedoic acid, a first-in-class antihyperlipidemic drug that targets adenosine triphosphate-citrate lyase enzyme to inhibit cholesterol synthesis. We also studied the modulation of multiple AMPK signalling pathways by bempedoic acid in a chronic hypertension model in rats. Sixty male Sprague-Dawley rats were divided into four groups: sham group, hypertensive group, standard captopril group, and bempedoic treated group. All groups underwent left renal artery ligation except the sham group. Fourteen days post-surgery, captopril and bempedoic acid were administered with a dose of 30 mg/kg/day orally to captopril-standard and bempedoic acid-treated groups for two weeks, respectively. In mesenteric resistance arteries, bempedoic acid activated AMPK energy independently and augmented AMPK multiple cellular targets to adapt to Ang II-induced cellular stress. It exerted antioxidant activity, increased endothelial nitric oxide synthase, and reversed the ER stress. Bempedoic acid maintained vascular integrity and prevented vascular remodelling by inhibiting extracellular signal-regulated kinase (ERK)/transforming growth factor-β fibrotic pathway. These effects were reflected in the improved hemodynamic measurements.

Keywords:  AMPK; Angiotensin II; Bempedoic acid; Hypertension

DOI:  https://doi.org/10.1016/j.lfs.2023.121573
Int J Mol Med. 2023 Apr;pii: 34. [Epub ahead of print]51(4):

Free fatty acids induce coronary microvascular dysfunction via inhibition of the AMPK/KLF2/eNOS signaling pathway.

Yanda Zhang, Jian Zhao, Changzhen Ren, Bowen Hu, Ru Ding, Zhiqing He, Chun Liang.

  Increased levels of serum free fatty acids (FFAs) are closely associated with microvascular dysfunction. In our previous study, a coronary microvascular dysfunction (CMD) model was successfully established via lipid infusion to increase the levels of serum FFAs in mice. However, the underlying mechanisms remained poorly understood. Therefore, the aim of the present study was to explore the mechanism underlying FFA‑induced CMD. A CMD mouse model was established via lipid combined with heparin infusion for 6 h to increase the concentration of serum FFAs. Following the establishment of the model, the coronary flow reserve (CFR), extent of leukocyte activation and cardiac microvascular structures were assessed in the mice. Cardiac microvascular endothelial cells (CMECs) were treated with different concentrations of palmitic acid and cell viability was evaluated. Changes in the expression levels of AMP‑activated protein kinase (AMPK), Krüppel‑like factor 2 (KLF2) and endothelial nitric oxide synthase (eNOS) were identified by immunohistochemical and western blot analyses. Experiments using AMPK activator, KLF2 overexpression plasmid, small interfering RNAs and nicorandil were subsequently designed to investigate the potential involvement of the AMPK/KLF2/eNOS signaling pathway. These experiments revealed that FFAs could induce CMD in mice, which was characterized by reduced CFR (1.89±0.37 vs. 2.74±0.30) and increased leukocyte adhesion (4,350±1,057.5 vs. 11.8±5.4 cells/mm2) compared with the control mice. CD11b expression and intracellular reactive oxygen species (ROS) levels were increased in CMD model mice compared with control mice. Serum TNF‑α and IL‑6 levels were higher in the model group than in the control group. Transmission electron microscopy revealed that CMECs in heart tissues of model mice were severely swollen. In addition, palmitic acid decreased CMEC viability and increased ROS production in a dose‑dependent manner. Notably, the AMPK/KLF2/eNOS signaling pathway was demonstrated to be suppressed by FFAs both in vivo and in vitro. Activation of this axis with AMPK activator, KLF2 overexpression plasmid or nicorandil restored the CFR in CMD model mice, inhibited oxidative stress and increased CMEC viability. Taken together, the results of the present study demonstrated that FFAs could induce CMD via inhibition of the AMPK/KLF2/eNOS signaling pathway, whereas activation of this pathway led to the alleviation of FFA‑induced CMD, which may be a therapeutic option for CMD.

Keywords:  AMP‑activated protein kinase; Krüppel‑like factor 2; coronary microvascular dysfunction; endothelial nitric oxide synthase; free fatty acids; nicorandil

DOI:  https://doi.org/10.3892/ijmm.2023.5237
Cell Commun Signal. 2023 Mar 13. 21(1): 55

FGF19 increases mitochondrial biogenesis and fusion in chondrocytes via the AMPKα-p38/MAPK pathway.

Shiyi Kan, Caixia Pi, Li Zhang, Daimo Guo, Zhixing Niu, Yang Liu, Mengmeng Duan, Xiahua Pu, Mingru Bai, Chenchen Zhou, Demao Zhang, Jing Xie.

  Fibroblast growth factor 19 (FGF19) is recognized to play an essential role in cartilage development and physiology, and has emerged as a potential therapeutic target for skeletal metabolic diseases. However, FGF19-mediated cellular behavior in chondrocytes remains a big challenge. In the current study, we aimed to investigate the role of FGF19 on chondrocytes by characterizing mitochondrial biogenesis and fission-fusion dynamic equilibrium and exploring the underlying mechanism. We first found that FGF19 enhanced mitochondrial biogenesis in chondrocytes with the help of β Klotho (KLB), a vital accessory protein for assisting the binding of FGF19 to its receptor, and the enhanced biogenesis accompanied with a fusion of mitochondria, reflecting in the elongation of individual mitochondria and the up-regulation of mitochondrial fusion proteins. We then revealed that FGF19-mediated mitochondrial biogenesis and fusion required the binding of FGF19 to the membrane receptor, FGFR4, and the activation of AMP-activated protein kinase alpha (AMPKα)/peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α)/sirtuin 1 (SIRT1) axis. Finally, we demonstrated that FGF19-mediated mitochondrial biogenesis and fusion was mainly dependent on the activation of p-p38 signaling. Inhibition of p38 signaling largely reduced the high expression of AMPKα/PGC-1α/SIRT1 axis, decreased the up-regulation of mitochondrial fusion proteins and impaired the enhancement of mitochondrial network morphology in chondrocytes induced by FGF19. Taking together, our results indicate that FGF19 could increase mitochondrial biogenesis and fusion via AMPKα-p38/MAPK signaling, which enlarge the understanding of FGF19 on chondrocyte metabolism. Video Abstract.

Keywords:  Chondrocyte; FGF19; Mitochondrial biogenesis; Mitochondrial fission–fusion; p38/MAPK signaling

DOI:  https://doi.org/10.1186/s12964-023-01069-5
Theranostics. 2023 ;13(4): 1247-1263

Proteomes from AMPK-inhibited peripheral blood mononuclear cells suppress the progression of breast cancer and bone metastasis.

Kexin Li, Xun Sun, Kazumasa Minami, Keisuke Tamari, Kazuhiko Ogawa, Hudie Li, Hailan Ma, Meng Zhou, Sungsoo Na, Bai-Yan Li, Hiroki Yokota.

  Background: During a developmental process, embryos employ varying tactics to remove unwanted cells. Using a procedure analogous to some of the embryonic cells, we generated a tumor-eliminating conditioned medium (CM) from AMPK-inhibited lymphocytes and monocytes in peripheral blood mononuclear cells (PBMCs). Methods: AMPK signaling was inhibited by the application of a pharmacological agent, Dorsomorphin, and the therapeutic effects of their conditioned medium (CM) were evaluated using in vitro cell cultures, ex vivo breast cancer tissues, and a mouse model of mammary tumors and tumor-induced osteolysis. The regulatory mechanism was evaluated using mass spectrometry-based proteomics, Western blotting, immunoprecipitation, gene overexpression, and RNA interference. Results: While AMPK signaling acted mostly anti-tumorigenic, we paradoxically inhibited it to build induced tumor-suppressing cells and their tumor-eliminating CM. In a mouse model of breast cancer, the application of AMPK-inhibited lymphocyte-derived CM reduced mammary tumors additively to a chemotherapeutic agent, Taxol. It also prevented bone loss in the tumor-bearing tibia. Furthermore, the application of CM from the patient-derived peripheral blood diminished ex vivo breast cancer tissues isolated from the same patients. Notably, proteins enriched in CM included Moesin (MSN), Enolase 1 (ENO1), and polyA-binding protein 1 (PABPC1), which are considered tumorigenic in many types of cancer. The tumor-suppressing actions of MSN and ENO1 were at least in part mediated by Metadherin (Mtdh), which is known to promote metastatic seeding. Conclusion: We demonstrated that PBMCs can be used to generate tumor-suppressive proteomes, and extracellular tumor-suppressing proteins such as MSN, ENO1, and PABPC1 are converted from tumor-promoting factors inside cancer cells. The results support the possibility of developing autologous blood-based therapy, in which tumor-suppressing proteins are enriched in engineered PBMC-derived CM by the inhibition of AMPK signaling.

Keywords:  AMPK; Metadherin; PBMCs; breast cancer bone metastasis; conditioned medium

DOI:  https://doi.org/10.7150/thno.80294